Management of stable coronary artery disease - ResearchGate

Introduction

Ischemic heart disease (IHD) is diagnosed when apatient presents one or more symptoms, signs or com-plications from an inadequate blood supply to my-ocardium.1 This is generally caused by obstruction ofthe coronary arteries for atherosclerosis and it gener-ally manifests itself with angina.2,3 Other symptoms,called ischemic equivalents, are known and can be ap-preciated as breathlessness, sweating, chest discom-fort, shoulder pain, palpitations, jaw pain. If one of

these symptoms appears predictably and reproduciblyat a certain level of exertion and it is relieved with restor nitroglycerine, stable angina is a more appropriatedefinition. Severity of symptoms is focused on theclassification of the Canadian Cardiovascular Society4

(Table 1).Therefore, different phases of coronary heart dis-

ease (CHD) are included in IHD with the exception ofacute coronary syndrome. Actually, patients with ahistory of obstructive or non-obstructive coronary ar-tery disease, who have become asymptomatic withtreatment and need regular follow-up, belong to thiscategory either.5

Narrowing of 70% or more in at least one maincoronary artery has traditionally represented the patho-physiological mechanism underlying stable IHD, caus-ing exercise and stress-related symptoms. Howeverstable IHD is more complex and physiopathology isbased on different mechanisms.6 Microvascular dys-function should be considered when a patient with sta-ble angina shows an insignificant coronaryangiography. Specific diseases can also provoke mi-crovascular disease, such as hypertrophic cardiomyopa-thy or aortic stenosis. In these cases, it is moreappropriate to define them as secondary coronary mi-crovascular disease. Focal or diffuse spasm of normalor non-obstructive plaque-diseased artery can be appre-ciated in patients with angina unrelated to certain levelof exertion. In this case pain episodes occur usually atnight and in the early morning. Nitrates generally re-

Management of stable coronary artery disease:from evidence to clinical practice

Riccardo Gerloni,1 Luciano Mucci,2 Tiziana Ciarambino,3 Manuel Ventura,4 Valeria Baglio,5 Massimiliano Chiuch,5Francesca Saladini,6 Stefania Dorigoni,7 Davide Tizzani,8 Paola Gnerre9

1Emergency Medicine, Cattinara Hospital, Trieste; 2Internal Medicine, Santa Croce Hospital, Fano (PU); 3Internal Medicine,Marcianise Hospital, Caserta; 4General Medicine, Ospedale degli Infermi, Rivoli (TO); 5Medical Clinic, Cattinara Hospital,Trieste; 6Department of Cardiology, Camposampiero Hospital, Padova; 7Internal Medicine, Santa Chiara Hospital, Trento;8Emergency and Surgery Medicine, Ospedale degli Infermi, Rivoli (TO); 9Internal Medicine, San Paolo Hospital, Savona,Italy

ABSTRACT

Ischemic heart disease, the leading cause of death, is extremely diffuse among patients hospitalized in Internal Medicineward so that Internist should be able to manage correctly this disease. The following review revises the most recent literatureand offers a practical clinical guide to be confident on this topic. After having emphasized that clinical overview remains es-sential, it briefly mentions advantages and limits of different investigations, reminds readers of possible alternative etiopatho-geneses of ischemic heart disease (cardiac syndrome X), reports the most appropriate medical therapy, and gives the opportunityto understand appropriateness of specialist strategies such as coronary artery by-pass grafting and percutaneous coronary inter-vention. Finally, it illustrates a rational and evidence-based follow-up of these patients, considering that only a small part ofthem should be followed by a Cardiologist. The aim of a correct management of ischemic heart disease remains to reduce mor-tality and improve the quality of life.

Correspondence: Paola Gnerre, Internal Medicine, San PaoloHospital, via Genova 30, 17100 Savona, Italy. Tel.: +30.019.8404082. E-mail: [email protected]

Key words: Ischemic heart disease; stable coronary artery dis-ease; angina.

Received for publication: 30 June 2016.Revision received: 10 August 2016.Accepted for publication: 17 August 2016.

This work is licensed under a Creative Commons AttributionNonCommercial 4.0 License (CC BY-NC 4.0).

©Copyright R. Gerloni et al., 2017Licensee PAGEPress, ItalyItalian Journal of Medicine 2017; 11:114-133doi:10.4081/itjm.2017.755

[page 114] [Italian Journal of Medicine 2017; 11:755]

Italian Journal of Medicine 2017; volume 11:114-133

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lieve symptoms within minutes and the electrocardio-gram (ECG) shows ST elevation. Finally left ventricu-lar dysfunction secondary to prior acute myocardialnecrosis is another sort of manifestation of stable IHD.

For all these reasons it is quite difficult to estimatethe incidence of IHD because it depends on setting ofpathology. The Health Survey for England reportedthat around 8% of men and 3% of women aged be-tween 55 and 64 years currently have or have hadangina. This estimate reaches up to 14% and 8% re-spectively if you consider men and women aged be-tween 65 and 74 years.7 For the same reason prognosisdepends on the characteristics of selected patients.Generally, estimates of annual mortality rates rangefrom 1.2 to 2.4% with an annual incidence of cardiacdeath between 0.6 and 1.4%.8-13

Clinical overview and the pre-test risk

A correct clinical overview is based on accuratemedical history. Clinician should distinguish typicalpain from atypical form. According to a classificationof the clinical symptoms we can consider:14 i) typicalangina if the pain answers to the characteristics listedabove: location (retrosternal), quality (oppressive), eti-ology (exercise or emotional stress), duration (severalminutes) and remission (rest or nitrates); ii) atypicalangina, differs from typical angina for the absence ofprecipitating factors. Pain often starts at rest with alow level of intensity. In case it increases slowly, itreaches its peak for a maximum of 15 min and then itdecreases, an underlying vasospasm can be consid-ered. An atypical presentation for location and quality,caused by physical effort, but unresponsive to nitrates,may underlie a microvascular etiology; iii) nonanginalpain, linked to non-cardiac causes.

The Bayesian approach uses clinical estimates ofpre-test disease (test PTP: termed pre-probability)along with the diagnostic tests results to generate in-dividualized probabilities of post-test disease. ForCHD clinical estimates of pre-test disease are influ-enced by the prevalence of disease in the studied pop-ulation, in addition to the clinical characteristics of thepatient (age, gender and nature of the symptoms).15

The sensitivity and specificity of a test are influencedby the characteristics of the population on which thetest is performed, therefore by the PTP.

The new European Society of Cardiology (ESC)Guidelines on chronic CHD6 starts from PTP to drawa correct diagnostic process for patients with stablechest pain. The PTP is calculated by crossing age, gen-der and patients’ symptoms.

Non-invasive tests for CHD have a sensitivity andspecificity of around 85%; so we will get less misdi-agnosis, avoiding testing on patients with PTP <15%(data for healthy people) or PTP >85% (data for sickpeople): in these patients, tests should be performedonly for specific and compelling reasons.

ECG exercise testing has low sensitivity (about50%), for which the number of tests with false resultis unacceptable in the population with PTP>65%.Based on this assumption, ESC guidelines6 suggest aflow chart for the diagnostic and therapeutic manage-ment of chronic CHD (Figure 1). The flow chart can-not be applied to patients: i) not candidates forcoronary angiography (for which there is indication tomedical treatment and to possible further diagnosticstudy); ii) with symptoms compatible with unstableangina (for which it is necessary to refer to the specificguidelines); iii) with typical symptoms and ejectionfraction <50% (for which there is indication for coro-nary angiography).

For patients with PTP <15% we should considerother non-cardiac chest pain causes and should notperform specific non-invasive stress-tests. Vasospasticangina should be considered and treated.

Patients with PTP between 15% and 85% shouldperform cardiac stress tests, in particularly imagingstress tests. The ECG exercise testing can be evaluatedif the PTP is between 15% and 65% or other methodsare not available.

For patients with PTP >85% CHD diagnosisshould be clinical and additional tests do not increasethe accuracy.

Coronary computed tomography angiography(CCTA) could also be an alternative to stress tests inpatients with a low PTP (between 15 and 50%)16 forits high negative predictive value.

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Management of stable coronary artery disease

Table 1. Severity of angina according to Canadian Cardiovascular Society.

Class I (no limitation of ordinary activity) Angina reproduced with strenuous exertion

Class II (slight limitation of ordinary activity) Angina reproduced on walking rapidly

Class III (marked limitation of ordinary activity) Angina reproduced on walking 100-200 m

Class IV (inability of activity) Angina reproduced for any activity

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Biochemical tests, non-invasive cardiacand coronary investigations

Biochemical tests are recommended to identify car-diovascular risk factors and to determine prognosis. Ac-tually hyperglycemia, dyslipidemia, thyroid disordersand kidney dysfunction should be assessed in every pa-tient with suspected coronary artery disease.6,17

Troponin seems to have a prognostic value in pa-tients with stable coronary disease. The increasedplasma concentrations could be a predictor of futureevents (myocardial infarction or death), but it has nosufficient independent prognostic value in out-of-hos-pital patients.18-20

Other biomarkers such as natriuretic peptide, C-reactive protein or genetic testing show conflicting re-sults to determine prognosis of stable coronary arterydisease.21,22

Resting electrocardiographyResting ECG can show previous myocardial in-

farction with Q waves, or abnormal ventricular repo-larization pattern. Anyway, a normal resting ECG isnot uncommon even in patients with chronicischemia.17,23

The Report of the American College of Cardiologyidentified a worse prognosis for patients presenting ECGpatterns with Q waves in multiple leads or an R wave inV1 indicating a posterior infarction, persistent ST-T-wave inversions, particularly in leads V1 to V3; left bun-dle-branch block (LBBB), bifascicular block, second-or third-degree atrioventricular block, ventricular tach-yarrhythmia, left ventricular (LV) hypertrophy.17

Resting echocardiographyAccording to 2006 ESC Guidelines, the role of

resting echocardiography is to detect or rule out dis-


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Figure 1. A correct clinical overview of chest pain. PTP, termed pre-probability; ECG, electrocardiogram. Adapted fromMontalescot et al., 2013.6

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orders such as valvular dysfunctions or hypertrophiccardiomyopathy and to evaluate left ventricular func-tion. Moreover, the development of tissue Doppler im-aging and strain rate measurements gives thepossibility to evaluate diastolic function.24 The authorsof the most recent ESC guidelines6 confirm the indi-cations mentioned above. Echocardiography shouldbe performed in all patients with symptoms of stablecoronary artery disease, because identification of LVfunction stratifies risk6 and, particularly, long-termsurvival. An ejection fraction (EF) <50% is recognizedto be associated with an annual mortality >3%.6 Theseaspects are underlined also in the Canadian and Brazil-ian Guidelines,4,25 where it is emphasized that kineticalterations can facilitate diagnosis as they can bemarkers of previous myocardial infarct or ongoing is-chemia. Echocardiography can also detect complica-tion of IHD such as ventricle thrombosis in akineticsegments, ventricle remodeling and particularlyaneurysmatic deformation, functional mitral regurgi-tation secondary to myocardial infarction.26 In case ofinsufficient echo quality, microbubble infusion maybe a useful adjunct for a better evaluation of wall mo-tion and perfusion, in order to calculate wall motionscore index.25,27

Coronary computed tomography angiographyand calcium scoring

Patients with a low-intermediate risk of obstructiveCHD (15-50%) can be investigated with CCTA.6,17

They should not be obese, without breath holding ca-pabilities; they should be in sinus rhythm with apreferably heart rate of 65-60 b.p.m. (β-blockers orothers rate-lowering medication can be used beforethe exam) and with a favorable calcium score (Agat-son <400).6,17-20 All these precautions permit goodquality images.

Measurement of calcium scoring is calculated asthe product of the coronary artery calcium area bymaximal plaque density (in Hounsfield units) and cal-cified lesions are quantified using Agatson score. Cal-cium score is useful for risk assessment inasymptomatic individuals, identifying the presence ofcoronary atherosclerosis, but it poorly correlates withnarrowing of the lumen, especially in young individ-uals with acute symptoms (who can have a coronaryartery calcification score of zero) and in patients withAgatson score >400 (stenosis can be overesti-mated).6,17,18

Exercise or pharmacological stressechocardiography

Exercise testing with echocardiography is usefulto identify the presence, location and extension of my-ocardial ischemia, during stress test an appropriate bi-

cycle ergometer is used and images are acquired at restand at each stage of exercise, including peak. Sensi-tivity and specificity for detection of coronary arterydisease range from 53 to 93% and from 70 to 100%respectively.1 The use of injectable agents is describedas valuable for a better identification of myocardialperfusion, while tissue Doppler and strain rate im-prove the capability to detect ischemia. TissueDoppler imaging allows regional quantification of my-ocardial motion (velocity), while strain (difference invelocities between adjacent regions) and strain rate(difference per unit length) allow determination of re-gional deformation.1 In patients unable to perform ex-ercise, pharmacological stress test may be performed.Two different approaches are suggested:24 i) infusionof short-acting sympathomimetic drugs such as dobu-tamine in incremental dose protocol which increasesmyocardial oxygen consumption similarly to physicalexercise; ii) infusion of coronary vasodilator agents(i.e., dipyridamole, adenosine) which provides a con-trast between regions supplied by non-pathologicalcoronary arteries (where perfusion increases) and re-gions supplied by stenotic arteries (where a lower in-crease or a decrease of perfusion is predictable).24

Brazilian Guidelines25 report different sensitivity fordifferent stress agent used, in the presence of one-ves-sel disease: 38% for dipyridamole, 70% for exercisestress test, 61% for dobutamine stress test; the additionof atropine to dobutamine is suggested to improve ac-curacy and decreases the rate of ineffective test, espe-cially in patients taking β-blockers.25 In contrast to2006 guidelines, 2013 ESC Guidelines6 considerdobutamine the pharmacological agent of choice toproduce supply-demand mismatch and suggest the useof contrast media and microbubbles to assess myocar-dial perfusion. Their use is considered as mandatorywhen two or more segments are not well visualized atrest.6 Tissue Doppler imaging and strain rate imagingare valuable to improve the diagnostic performance ofstress echocardiography to detect ischemia.6 Stress im-aging compared to exercise ECG test has a superiordiagnostic performance (for stress echo sensitivity 80-85%, specificity 80-88%, vs for exercise ECG 40-45%and 85-90% respectively), ability to quantify and lo-calize areas of ischemia and to provide diagnostic andprognostic information in patients with ECG abnor-malities, particularly in those with previous coronaryartery disease.26-28

As it is mentioned in 2013 ESC guidelines, phys-ical stress test is preferable to pharmacological one,because the former gives information such as exerciseand work load, changes in heart rate and blood pres-sure.6 Regional wall motion abnormalities at rest andinability to perform exercise adequately are the onlytwo situations to prefer pharmacological stress test.

In the American Heart Association (AHA) 2014



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Guideline for the diagnosis and management of patientswith stable IHD there is no mention of non-invasive ex-aminations as resting or stress echocardiography.29

Cardiac magnetic resonance at restand stress testing

Cardiac magnetic resonance (CMR) can be per-formed at rest or as stress test, using dobutamine infu-sion (to detect wall motion abnormalities induced byischemia) or vasodilator agents like adenosine. More-over, CMR can be useful to assess coronary anatomy(magnetic resonance coronary angiography).6

CMR can be useful in the detection of CHD and,particularly, in assessing myocardial viability, detectionof small subendocardial infarctions and ventricular func-tion before revascularization, risk stratification in sus-pected CHD and evaluation of myocardial ischemia.30

Main and appropriate recommendations on the useof CMR are:31 i) detection of CHD in symptomatic pa-tients: evaluation of chest pain syndrome using va-sodilator perfusion CMR or dobutamine stressfunction CMR and MR coronary angiography; ii) riskassessment of CHD in previous coronary angiography(catheterization or CT) with stenosis of unclear sig-nificance, using vasodilator perfusion CMR or dobu-tamine stress function CMR; iii) detection ofmyocardial scar and viability, using late Gadoliniumenhancement.

Electrocardiogram exercise testing

Stress ECG is a widespread test, used both for IHDdiagnosis and event risk stratification (Duke Treadmillscore).32,33 It is performed by treadmill or bicycle ex-ercise, recording a 12-lead ECG.

The exam is diagnostic when recording ECGdemonstrates a depression ≥0.1 mV, persisting for atleast 0.06-0.08 s after the J-point, in one or more ECGleads at peak exercise or during recovering. High riskof mortality is present in patients whose ST-segmentdepression appears at a reduced workload or persistsinto recover. Important additional non-ECG factors areexercise duration, chronotropic incompetence, angina,ventricular arrhythmias, heart rate recovery, and hemo-dynamic response to exercise (i.e., drop in systolicblood pressure), or when combination scores such asthe Duke Treadmill or Lauer scores are applied.17

The exercise stress test should be stopped for thefollowing reasons: symptoms limitation, combinationof symptoms such as pain with significant ST-changes; marked ST-depression, ST-elevation >1 mm,significant arrhythmia, sustained fall in systolic bloodpressure >10 mmHg, marked hypertension (>250mmHg systolic or >115 mmHg diastolic); achieve-ment of maximum predicted heart rate. Limitations tothe correct interpretation of the test are the presence

of LBBB, paced rhythm and Wolff Parkinson White(WPW) syndrome, because in these cases ECGchanges cannot be evaluated. Additionally, false pos-itive results are more frequent in patients with abnor-mal resting ECG for left ventricular hypertrophy(LVH), electrolyte imbalance, intraventricular conduc-tion abnormalities and use of digitalis. Antianginaltherapy should be stopped for 24-48 h before test. Itis not diagnostic if at least 85% of maximum heart rateis not achieved.24

Exercise stress testing can also be useful to evaluatethe efficacy of treatment, to assist prescription of exer-cise after control of symptoms, to calculate the patient’sevent risk (using Duke Treadmill score that combinesexercise time, ST-deviation and angina).34-37

Single-photon emission computed tomographymyocardial perfusion imaging, stress perfusionscintigraphy and positron emission tomography

Myocardial perfusion single-photon emissioncomputed tomography myocardial perfusion imaging(SPECT) is generally performed using Tc-99m or Tl-201 and it is conducted by using vasodilator agents(adenosine or regadenoson, dipyridamole) or dobuta-mine. The major limit is high radiation exposure. My-ocardial hypoperfusion is characterized by reducedtracer uptake at rest or after stress. Stress perfusionscintigraphy is usually ECG-gated SPECT that addsadditional information about ejection fraction and leftventricular motility. Another important rule of SPECTis to assess myocardial viability, evaluating radionu-clides distribution after nitrate administration.

Brindis et al.38 defined the following main appro-priate criteria of SPECT myocardial perfusion imag-ing: i) detection of CHD in asymptomatic andsymptomatic patients (evaluation of chest pain syn-drome) when PTP is intermediate; ii) risk assessmentwith prior test results: worsening of the symptoms, orfollow-up in stable disease; iii) risk assessment withprior test results in unstable angina/non ST-elevationmyocardial infarction (NSTEMI), STEMI, pre-oper-ative or post-revascularization [percutaneous coronaryintervention (PCI) or coronary artery bypass grafting(CABG)]; iv) risk assessment with prior test results:prior coronary calcium Agatston Score greater than orequal to 400; v) assessment of viability/ischemia: is-chemic cardiomyopathy (including SPECT imagingfor wall motion and ventricular function) in patientseligible for revascularization.

In comparison with SPECT, positron emission to-mography (PET) is less available and more expensive.However, it offers a high sensitivity technique in thedetection of CHD (in particular microvascular dis-ease), quantifying myocardial blood flow usingpositron-emitting radiotracers (like 82Rubidium or 13N-ammonia).39,40


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Management of stable ischemic heart disease

Symptoms control, improved survival and preven-tion of cardiovascular events are the main aims of ther-apy in patients affected by stable IHD.41,42 Optimalmanagement requires risk factors control (such as treat-ment of hypertension, dyslipidemia and diabetes mel-litus, cessation of smoking, weight reduction, stressreduction), regular physical activity and therapies as-sumption, such as antianginal and antiplatelet drugs.43,44

β-blockers, used as first line therapy, improve ex-ercise tolerance and reduce anginal episodes by limit-ing oxygen consumption for their inotropic andchronotropic action, and increasing perfusion of is-chemic areas for diastole prolongation. Further, theyimprove survival in patients with stable coronary dis-ease with systolic heart failure or previous myocardialinfarction. In contrast, there is not enough evidencethat β-blockers reduce the risk of death in patients withstable coronary heart disease in the absence of recentmyocardial infarction or heart failure.45,46 β-blockersmay be used in combination with dihydropyridines(DHP) calcium channel blockers, but they should beavoided in combination with non-DHPs, due to therisk of bradycardia or atrioventricular block.6 Further,they should not be used in patients with vasospasticor variant (Prinzmetal’s) angina, because they may in-duce coronary vasospasm.

Calcium channel blockers are generally used assecond line therapy when β-blockers cause side effectsor are contraindicated. Calcium channel blockers de-crease contractility and induce coronary and periph-eral vasodilatation, reducing peripheral vascularresistance.47 Non-DHPs reduce also the heart rate in-hibiting sinus node. Verapamil is used in all varietiesof angina - effort, vasospastic, unstable - supraventric-ular tachycardia and hypertension. DHPs may be usedin association with β-blockers due to greater antiang-inal effect, even if this combination is oftenunderused.48

Nitrates induce coronary arteriolar and venous va-sodilatation by means of their active component nitricoxide, so reducing the preload. Nitrates may be short-acting or long acting. Long-acting nitrates are used forangina prophylaxis, but they are not continuously ef-fective if taken over a prolonged period, because theyinduce tolerance that should be prevented by changesin dosing and timing of administration or using slow-release preparations.49-51

Ranolazine, a late sodium channel blocker, is an-other antianginal agent without influences on bloodpressure and heart rate, used alone or in combinationwith β blockers.52 It is used in patients intolerant ornon-responders to first-line agents as β-blockers orcalcium antagonists. QTc should be monitored be-cause ranolazine prolongs QT duration. In patients

with stable chronic angina, ranolazine reduces recur-rent ischemia53 and improves HbA1C in diabetics fora better insulin secretion.54,55 Improvement of patientswith chronic angina is demonstrated in a series of tri-als which consider different outcomes such as exercisestress test performance (duration, time to angina, timeto ST-segment depression),56-58 quality of life,59 andfrequency of angina with need for nitroglyercin.60-62

Ranolazine is well tolerated and its most frequent ad-verse events reported were dizziness (11.8%), consti-pation (10.9%), and peripheral edema (8.3%).63

Ranolazine is contraindicated with potent inhibitorsof the CYP3A4 pathway including certain antifungals(ketoconazole and other azole class), antibiotics(macrolides, clarithromycin), HIV protease inhibitors,diltiazem, and grapefruit products.64

Ivabradine reduces heart rate, inhibiting the sinusnode pacemaking current. So, it decreases myocardialoxygen demand without effects on blood pressure andcontractility. Its use is approved for therapy of chronicstable angina in patients intolerant to β-blockers or un-controlled by the latter, because it reduces heart rateand the number of angina attacks.65 It decreases symp-toms in patients with stable angina pectoris and im-proves outcomes in patients with systolic heartfailure.66-68 Ivabradine is shown to reduce disability,by limiting angina episodes and disease perception.As recently demonstrated in a substudy,69 this positivedrug effect is maintained over 3 years of follow-upand the best improvement is evident for patients in thelowest tertile for angina frequency score at baseline.Statistical analyses also reveal an improvement inphysical limitation at 6 months, despite this datumloses its statistical significance on time. However, inthis substudy a positive trend on angina-related qualityof life emerges for patients treated with ivabradine andthis aspect should be kept in mind by Internists whogenerally deal with very old patients.

Nicorandil is a nitrate derivative of nicotinamidethat can be used for the prevention and long-termtreatment of angina. This drug dilates epicardial coro-nary arteries and stimulating ATP-sensitive potassiumchannels in smooth muscle cells of blood vessels. Theprospective study IONA (impact of nicorandil inangina) reported a reduction of cardiovascular events(such as coronary heart disease death, non-fatal my-ocardial infarction, or unplanned hospitalization forcardiac chest pain) by 14% in 2565 patients takingNicorandil (against 2561 patients assessed to placebo)in follow up for an average of 1.6 years (range 1-3years).70,71

Other antianginal drugs, such as allopurinol, mol-sidomine and trimetazidine, may be used on few evi-dence of their efficacy. Finally, antiplatelet agents areused in the prevention of vascular events. If there areno contraindications, all patients with stable angina



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pectoris are treated with aspirin. Patients allergic toaspirin can be treated with clopidogrel - antagonist ofthe platelet ADP receptor P2Y12.72 Prasugrel and tica-grelor have not been evaluated in patients with stableangina. Finally, combined antiplatelet therapy is ben-eficial in patients with stable angina who have under-gone elective PCI. Patients with documented CHDhave a very high risk of cardiovascular events and re-ceive benefits from statins treatment (LDL-C target of1.8 mmol/L or 70 mg/dL).73 Statins can reduce mor-tality and the incidence of acute coronary syndromes;in addition, there is increasing evidence that they re-duce the incidence of anginal episodes in patients withstable IHD. In the AVERT trial, patients treated withatorvastatin had a reduction in the rate of hospitaliza-tion for worsening angina compared to patients treatedwith angioplasty and without statins.74 In the DUAALtrial, patients with stable IHD were randomly assignedto one of three treatments: amlodipine, atorvastatin oramlodipine plus atorvastatin. During 48 hours, pa-tients treated with atorvastatin had a reduction of is-chemic episodes and more than 50 percent of patientswere asymptomatic at 26 weeks.75 The use of ACE in-hibitors in stable IHD is controversial; actually clinicaltrials have not evenly demonstrated that the ACE in-hibitors reduce cardiovascular mortality, non-fatalheart attack, stroke and heart failure in patients withatherosclerosis and preserved left ventricularfunction.76 Instead, it is appropriate to use ACE in-hibitors in patients with stable angina if hypertension,chronic kidney disease, diabetes or ventricular dys-function (LVEF ≤40%) coexist.77

Invasive treatment of cardiac ischemia:coronary artery bypass grafting orpercutaneous coronary intervention?

In patients with refractory symptoms to medicaltreatment the choice is revascularization strategy, per-cutaneous or surgical revascularization.6 ThereforeCABG or PCI, may be indicated in flow-limiting coro-nary stenosis to reduce myocardial ischemia and its

adverse clinical manifestations.78-80 Subsisting similargoals, revascularization and medical therapy must beconsidered as complementary.

CABG was performed for the first time in 1964.81

The first PCI was introduced thirteen years later.82

Both revascularization techniques have improved inthe following years: CABG with the use of arterialconduits, PCI with the advent of stent.83

Both the procedures (CABG and PCI) presentrisks that are summarized in Table 2.84

Formulation of the best revascularization approachrequires interaction among cardiologists, cardiac sur-geons and the patient, who should be adequately in-formed.85

The choice among medical therapy, CABG or PCIdepends on the risk-benefit ratios of every strategy.Numerous models have been developed for risk strat-ification, based on anatomical complexity or clinicalrisk,86 such as the EuroSCORE, old and no moreused,87 the EuroSCORE II,88,89 the STS score90 forCABG surgery, the SYNTAX score,91 the NCDRCathPCI risk score,92 the ACEF model93 for PCI, theSYNTAX II score94 for comparing CABG with PCI,the ASCERT study,95 used to predict mortality at dif-ferent time point following CABG and PCI.96,97 Un-fortunately the variability of these models and theabsence of several important variables, such as frailty,physical independence and porcelain aorta, do not per-mit to identify one specific risk model, universally ac-cepted and validated. Therefore, the risk stratificationshould be used as a guide, while clinical judgment andmultidisciplinary dialogue remain essential.94

Several trials compared CABG with PCI, and ei-ther CABG and PCI with medical therapy. The bestresults occurred for PCI with use of the new-genera-tion drug-eluting stents and for CABG with maximaluse of arterial grafts.98

The majority of these studies have some limits: i)included only male patients who were relativelyyoung, with preserved left ventricular function andwithout previous revascularization; ii) the patientswere highly selected: they were randomized by delin-


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Table 2. Complications of revascularization procedures.

Coronary artery bypass grafting Angioplasty

Bleeding Emergency open-chest surgery

Stroke Stroke

Heart attack Heart attack

Death Death

Anesthesia problems* Hematoma

Local infections Coronary dissection

*Some people have memory loss and trouble thinking clearly, especially in the elderly, and these problems tend to improve several months after surgery.

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eation of coronary anatomy by angiography, withoutroutine assessment of ischemia; iii) the revasculariza-tion was performed when medical therapy failed; iv)the proportion of patients who did not undergo revas-cularization progressively declined during follow-up,camouflaging differences between the two strategies(CABG and PCI); v) time of follow-up was limited,usually less than five years: so reducing the possibleevaluations about the advantages of CABG related toarterial grafts.98

Medicines are the primary options for stable, low-risk CHD, and should be given to all CHD patients.Medically refractory is a useful high-risk marker ofpotential benefit from revascularization.

The COURAGE trial reported no difference indeath, myocardial infarction and stroke with PCI com-pared with medical therapy for stable angina. On theother hand, patients without angina were significantlymore numerous in the PCI group at one and three years.The difference was minor at five years, when patientsin both groups underwent additional revascularization(21% in the PCI group and 33% in the medical therapygroup respectively).99 Most of other meta-analyses donot describe differences between PCI and medical treat-ment in terms of death, myocardial infarction, un-planned revascularization or angina.100-103

The results in terms of rates of death, cardiac deathand non-fatal myocardial infarction are similar if com-paring early generation drug-eluting stents versus bare-metal stents, while a relative risk reduction in the needfor subsequent or repeat target vessel revascularizationwas registered with the use of drug-eluting stents.103,104

Compared with bare-metal stents and early gen-eration drug-eluting stents, new-generation drug-eluting stents have also improved safety outcomesincluding death, myocardial infarction and stentthrombosis.103,105-108

The superiority of CABG with internal mammaryartery to medical therapy for specific subset of CHD re-sulted into two meta-analyses that demonstrated sur-vival benefit in patients with left main or three-vesselCHD, particularly when the proximal left anterior de-scending coronary artery was involved. Benefits weregreater in patients with severe symptoms, early positiveexercise tests and impaired left ventricular func-tion.109,110

It is very difficult to choose between the two revas-cularization strategies (CABG or PCI), because neitherPCI nor CABG alone can provide a solution for the en-tire spectrum of CHD patients who need revasculariza-tion. CABG permits more complete revascularizationthan PCI, especially with chronic proximal occlusions.88

The choice of the most appropriate strategy of my-ocardial revascularization remains debatable in manypatients. Randomized trials comparing surgery(CABG) to angioplasty (PTCA) have shown that both

modalities are equivalent in terms of survival or in-farct free survival. In patients with type 2 diabetesmellitus in the BARI 2D Trial, a strategy of revascu-larization with CABG or PCI resulted in no differencein mortality compared with optimal medical therapy,111

but patients treated with PTCA required many moreadmissions for additional revascularization proceduresduring follow up, with increasing of the time awayfrom a normal active life, and increasing costs in thetreatment of proximal left anterior descending coro-nary artery disease112,113 and left main coronary arterydisease (in this case some trials demonstrated morerisk of stroke in the group treated with CABG).114,115

In case of three-vessel coronary artery disease, thestudies are discordant: a meta-analysis including pa-tients treated before the use of drug-eluting stentsdemonstrated no differences between PCI and CABGin terms of mortality in all patients, but with reducedmortality in diabetics and in aged 65 years or more pa-tients if treated with CABG.116 A following meta-analysis with patients treated with drug-eluting stentsreported a significant reduction in mortality, myocar-dial infarction and repeat revascularization in thosegroups performed with CABG, but with increasingrisk of stroke.117 There is notable consistency in thefindings on the survival advantage of CABG over PCIfor more severe three-vessel CHD.98

The decision to treat patients with CABG has beenlargely based on CHD extension and left ventricularfunction. Considering patients with stable and unsta-ble angina (excluding recent myocardial infarction),those with left main narrowing >50% or three-vesselstenoses >70%, or even two-vessel stenoses >70%,where one of the vessels is the proximal left anteriordescending, presented minor mortality if treated withCABG.118

Specific advantages of CABG include: revascular-ization of chronically occluded vessels with collateralssupplying viable myocardium, protection of territoriesrather than simply treating lesions, greater durabilityof conduits compared to bare-metal stents, while inthis case the difference with drug-eluting stents ispoor. Based on these principles, physiologic ratherthan anatomic considerations are most useful in deter-mining whether and how urgently to revascularize:STEMI is an emergent indication and high-risk non-STEMI an urgent indication. Coronary anatomy, in-cluding both number of vessels and lesioncharacteristics, continues to influence decision onreperfusion strategy and patient specific strategies.119

The majority of the PCI versus CABG trials en-rolled populations that were at relatively low risk forischemic clinical events. Trials demonstrated few hardoutcome (survival, MI, or stroke) differences betweenCABG and PCI. CABG continues to be the most suit-able revascularization option for patients with multi-



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vessel, multi-lesion CHD, PCI is the acute stabiliza-tion method of choice for patients with on-going is-chemia and acute MI, especially among patients withhemodynamic compromise, and/or major comorbidity.Bypass surgery remains the treatment of choice in di-abetics only in case of complex coronary anatomysuch as multi-vessel CHD, left main CHD and in pa-tients with multi-vessel disease and impaired ventri-cles.119

Cardiac syndrome X: angina pectoriswith normal coronary arteries

Cardiac syndrome X is a clinical syndrome thatrefers to patients with angina and normal coronary ar-tery, who can show evidence of coronary microvascu-lar dysfunction or abnormalities on stress testing.Microvascular dysfunction causing ischemia is due toendothelial cell dysfunction, abnormal cardiac adren-ergic tone and occult small vessel coronary artery dis-ease. The cardiac microvasculature may have areduced vasodilator, or even a paradoxical vasocon-strictor response to several pharmacologic agents andexercise.120 Because of these abnormalities, cardiacsyndrome X has also been called microvascularangina. Increased cardiac sympathetic tone121 and in-creased response to β-adrenergic stimulation122 cancontribute to autonomic system abnormalities. Actu-ally, enhanced sensitivity to intracardiac pain or theso-called sensitive heart syndrome may result fromsympathovagal imbalance with sympathetic predom-inance123 or reduced activity of the endogenous opioidsystem.124

Patients with cardiac syndrome X are younger thanthose with atherosclerotic cardiovascular disease andpredominantly female.125 In fact, myocardial ischemiaand/or coronary microvascular dysfunction is presentin 20 to 50 percent of women with chest pain and nor-mal coronary arteries.126 Patient with cardiac syn-drome X may have an acute coronary syndrome dueto a ruptured atheromatous plaque and no residual le-sions greater than 50 percent.127 Normal coronaryanatomy or vessels without ≥50 percent stenosis havebeen reported in 9-14% of patients with a non-ST el-evation ACS.128

Management

Considering patients with cardiac syndrome X, thechest pain is similar to classic angina pectoris in aboutone-half of them. It may be precipitated by effort, butalso occurs at rest.129 However, compared to no inter-vention, exercise training improved exercise capacityby 34 percent and delayed the onset of pain during ex-ercise by 100 percent, although the maximum painwas unchanged.130

The episodes are predominantly exertional, fre-quently occur from midnight to early morning andeach episode generally lasts 5 to 15 min. Many undi-agnosed patients with anginal type chest pain relievesymptoms with sublingual nitroglycerin.131 Tachycar-dia, hypertension, diaphoresis, and a gallop rhythmcan be noticed when symptoms are present.

A 12-lead ECG should be performed in all patientswith a history of chest pain. The ECG is usually nor-mal between episodes. Transient ECG changes, withST segment depression are common.132 The absenceof ECG changes does not exclude a cardiac etiology.ST-segment elevation, that is the hallmark of variant(Prinzmetal’s) angina, is not a feature of cardiac syn-drome X.133 Ambulatory ECG monitoring for 24 hmay be helpful for documenting ST segment changes.

The typical finding on the exercise ECG is hori-zontal or down-sloping ST segment depression. Exer-cise thallium-201 myocardial scintigraphy maydemonstrate regional myocardial perfusion defectsduring exercise.134 Studies have demonstrated neitherperfusion defects nor regional wall motion abnormal-ities after dobutamine or transesophageal atrialpacing,135 because the ischemia is limited to the suben-docardium.136

A coronary angiogram showing normal epicardialcoronary arteries (<30 percent diameter reduction) isnecessary to diagnose cardiac syndrome X. Lesionsbetween 30 and 50 percent may be evaluated with ei-ther fractional flow reserve or intravascular ultra-sound.137

Measurement of coronary flow reserve (CFR) canshow microvascular disease.138 CFR is the ratio of max-imal hyperemic coronary blood flow, measured after in-fusion of a coronary vasodilator such as adenosine ordipyridamole, to resting or basal coronary blood flow.Normal CFR ranges from 2.5 to 5. Occasionally it isgreater than 5. Maximal coronary blood flow should beat least 2.5 times the resting blood flow. CMR can beuseful for studying patients with a possible diagnosis ofcardiac syndrome X and it is able to detect regional dif-ferences in myocardial blood flow.139

LVH, right ventricular hypertrophy, stress inducedcardiomyopathy, systemic amyloidosis140 should beconsidered and exclude before diagnosing syndrome X.

Patients with cardiac syndrome X and stableangina generally have an excellent prognosis, whilethose with acute coronary syndromes have an appre-ciable acute mortality.141

All patients with cardiac syndrome X should betreated with aggressive risk factor reduction and sub-lingual nitroglycerin.

The 2013 ESC guidelines on the management ofstable coronary heart disease recommend that all pa-tients receive secondary prevention medications in-cluding aspirin and statins and that β blockers should


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be used as first line therapy.6 Calcium channel block-ers are used if β-blockers are not effective. Statinshave been shown to improve coronary artery endothe-lial function142 and β-blockers are most effective in re-ducing the frequency and severity of angina and inimproving exercise tolerance.143 Atenolol significantlyreduces anginal episodes and improves quality-of-lifemeasures.

Ranolazine is a novel anti-anginal agent and it re-sulted in significantly improved myocardial perfu-sion.144

Hormone replacement therapy may be beneficialin some postmenopausal women with chest pain andestrogen deficiency. Estrogen may act by improvingendothelium-dependent coronary vasomotion.145

Ace-inhibitors, imipramine and L-arginine andspinal cord stimulation have a secondary role in pa-tients who persist symptomatic.146

Follow up of patient with stable ischemic heartdisease

The management of stable IHD aims to relievesymptoms, to improve the quality of life and to reducethe risk of acute coronary syndrome, heart failure anddeath.

The literature has shown that a periodic follow-upof these patients reduces the individual cardiovascularrisk and increases the quality of life.147 However, norandomized trials assess the prognostic impact of dif-ferent follow-up strategies,6 therefore most of theguidance provided by the international literature andthe scientific community are based on expert opinionor on small retrospective studies or registries.

Guidelines recommend clinical evaluations everyfour to six months in the first year after the ischemicevent. After the first year, in patients with stable con-ditions, even in patients with important systolic dys-function, the follow-up can be performed every 6 to12 months, if the patient is enough reliable to call foran appointment in case symptoms or functional capac-ity become worse. This follow-up should be per-formed by a general practitioner, with possiblereference to a cardiologist in cases of doubts and un-certainties.6,17

Additional prospective studies are required to es-tablish appropriate follow up strategies and efficienttime intervals for evaluation. There is not yet a prog-nostic score for detection of patients with stable IHDwho are at high risk of major adverse cardiac events.Surely adverse outcomes are associated with time toischemia during exercise, frequency and severity ofangina, onset of recurrent symptoms <6 months, priorinfarction or CABG, resting ECG abnormalities, LVHor enlargement or abnormal function, coronary an-giography stenosis, diabetes mellitus, comorbidities,age, smoking and sex.17,148-150

The guidelines do not define precisely the ele-ments needed in follow-up visits. In general terms, theliterature suggests careful interval medical historyevaluation, limitations in physical activity, assessmentof symptoms and clinical and functional status, phys-ical examination (including measurement of weightand waist circumference and BMI, as well as bloodpressure and heart rate), and execution of first levellaboratory exams according to patient’s clinical eval-uation.6,17,147,151

Medical examination should consider adherenceto drug and behavioral therapy, onset of adverse ef-fects, monitoring of cardiovascular risk factors and co-morbidities, recurrence of ischemia, onset ofsymptoms and signs suggestive of heart failure, ar-rhythmias, heart valve disease and peripheral vasculardisease. The American guidelines suggest SAQ (Seat-tle angina questionnaire, a 19-item, self-reportedquestionnaire validated to quantify the symptoms,functional limitations and quality of life of patientswith stable IHD) as a tool for monitoring the patient’sclinical status.17

Glucose, creatinine, lipid profile and glycated he-moglobin in diabetic patients should be periodicallyevaluated. Blood count, serum electrolytes and thyroidfunction should be monitored annually.17,152

The serial measurement of natriuretic peptides (tooptimize the therapy in the case of a concurrent situa-tion of chronic heart failure) showed contrasting re-sults. However, it is demonstrated that high levels ofnatriuretic peptides are associated with worse progno-sis, instead their reduction is associated with a betterprognosis.6,153

Resting electrocardiogram should be performedannually, even in stable patients. A supplementaryelectrocardiogram should be performed in case ofanginal symptoms modification, onset of syncope orpre-syncope or symptoms compatible with arrhyth-mias, assumption of new drugs with possible second-ary abnormalities of electrical conduction.6

Echocardiography should be considered only incase of clinical suspicion: onset or worsening of heartfailure or valve disease, evidence of new ischemia.17,152

The American Guidelines do not suggest a periodicechocardiographic evaluation in case of stable diseaseor in low risk patients.17

Stress testing is appropriate in the presence of newor worsening symptoms, once unstable angina or acutecoronary syndrome have been excluded. The recom-mendations are similar to the ones used for the diag-nosis of suspected IHD. Therefore, a candidate totreadmill stress testing should have an interpretableresting ECG. If resting ECG is uninterpretable orshows LBBB, a stress echocardiography, or a myocar-dial scintigraphy or, as a second choice, a cardiac MRIshould be performed. These same exams should be



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considered as first choice in the event of high risk pa-tient or known multi-vessel diseases.17 CCTA could beconsidered in patients with previous CABG or previ-ous placement of stents >3 mm in order to assess theirpatency, in the context of absence of severe calcifica-tions.17

The international guidelines highlight the utility toperform the same test in the same patients to avoidtest-dependant discrepancies.

The appropriateness of performing non-invasivetesting in patients who are asymptomatic or have sta-ble symptoms depends on factors related to the likeli-hood of significant findings. There is no current datademonstrating that a follow-up strategy based on theuse of stress tests in patients persistently asympto-matic, would improve their outcomes.154,155

The management of patient with stableischemic heart diseaseRationale and objective

IHD is a frequent and disabling disease, associatedwith an appreciable incidence of acute coronary eventsand increased mortality. For this reason, Internistshould know how to treat these patients at best, refer-ring only a small part of them to Cardiologists. It isnecessary a great effort because therapy and invasivetreatments are continuously progressing and Clini-cians should be constantly updated. Therefore, thegoal of this work is to raise awareness of the clinicalmanagement of stable IHD through a better knowl-edge of the most recent revisions and guidelines.Some particular aspects will be omitted because theyare considered too specialistic and are already outlinedin the previous part of this monography.

Methodology

In order to provide evidence-based recommenda-tions for the management of patients with stable IHD,we first verified the existence of guidelines on thematter. Therefore, we conducted a search using thefollowing database-guidelines: i) Scottish Intercolle-giate Guidelines Network (SIGN); ii) Institute forClinical Systematic Improvement (ICSI); iii) NationalInstitute for Health and Clinical Excellence (NICE) -National Health System (NHS) evidence; iv) NationalGuideline Clearinghouse (NGC); v) Canadian Med-ical Association, CMA Infobase; vi) New ZealandGuidelines Group; vii) Italian National Health SystemGuidelines; viii) Clinical Practice Guidelines Portal;ix) eGuidelines.

The research was carried out by seven authors in-dependently, using the terms stable, ischemic, heart,disease as key words, when the site included thesearch function, and in other cases we listed the last

manually guidelines stored in the database. The re-sults obtained separately were then compared anddiscussed together. The guidelines thus obtainedwere evaluated using the AGREE instrument156 (Ap-praisal of Guidelines, Research and Evaluation II,22) by 4 authors independently. AGREE II assessescompliance with 23 requirements, meeting 6 do-mains as the explanation of the purpose, the clarity,the involvement of all stakeholders, the rigor of de-velopment, applicability and editorial independenceof the same. Each author assessed the compliance ofindividual requirements with a score from 1 (dis-agree completely) to 7 (complete agreement). Thescores assigned by each author were added within in-dividual domains and reported with the highest andthe lowest score possible within the domain based onthe number of requirements included and the numberof evaluators.

Results

Through the databases listed above, we identified4 guidelines which we evaluated with AGREE method(Table 3). Other references were excluded because toospecific and non-functional for our work. By usingAGREE criteria we judge the NICE guidelines157 onstable IHD to be the best.

Actually, it contains excellent description of targetpopulation, objectives and purpose, it does not forgetto consider target-population preferences. It empha-sizes the role of informed decisions on risks and ben-efits of different treatments. Further it underlinescultural lacks, unresolved questions of managementand it always suggests adequate trials to resolve theuncertainties. It is a complete guideline elaborated in468 pages; however, there is a shorter version, suitablefor clinicians.

ESC6 and AHA17 guidelines are both good guide-lines. ESC guidelines contain clear messages, elabo-rated with many tables and easy to access. However,there is not a precise description of the target popula-tion, there are not any considerations about possiblebarriers to guidelines implementation. Further, the


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Table 3. Evaluation of the guidelines on sepsis using theAppraisal of Guidelines, Research and Evaluation II(AGREE) method.

Guideline AGREE evaluation

National Institute for Health and Clinical Excellence (NICE) 81%

European Society of Cardiology (ESC) 57%

American Heart Association (AHA) 57%

Canadian Cardiovascular Society (CCS) 43%

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economic aspects are marginally described. AHA isschematic and easy to assess, but it lacks some impor-tant aspects: the process used to produce recommen-dation is not described, time and methods of guidelineupdate are ignored, the barriers to guideline imple-mentation are not considered.

Canadian Cardiovascular Society (CCS) Guide-lines4 are really synthetic and clear, but there are mod-est indications on the most recent non-invasive testsuch as MR and PET. They discuss marginally differ-ent revascularization approaches without consideringcost, risk and benefits. Barriers to guidelines imple-mentation are not mentioned; a precise description ofthe target population is absent.

The importance of a correct clinical overview

Management of stable angina needs great compe-tence and optimal clinical ability since the beginning.Actually, the most important approach is based on acorrect clinical overview, starting from symptoms re-ported analyses. Capacity of distinguishing typicalfrom atypical syndrome is the first necessary step re-quired.4 Indeed, risk factors (particularly age and gen-der) and symptoms permit to stratify pre-testprobability of disease.4,6 According to this result cli-nician can suggest to perform nothing or angiographyor a non-invasive test to demonstrate clinical suspectof angina. ECG exercise has not a great sensibility andis not advisable when pre-test probability is over 65%.Further, it should not be used in case of LVEF <50%,exercise limited by orthopedic or other non-cardiacproblems or equivocal ECG, such as LBBB, WPW orpaced rhythm.6,24 Obviously biochemical examinationand echocardiography are two precious tests whichcan facilitate the clinician’s approach. Actually, in caseof systolic dysfunction it is mandatory to know coro-nary anatomy and coronary angiography is preferredto CCTA when patient suffers from a typical chestpain.6 Troponin, if correctly used, can be helpful to cli-nician to distinguish acute coronary syndrome. In thiscase patient management and treatment are based onNSTEMI guidelines6 (Figure 2).

Main tests at first medical examination and duringfollow-up

Every patient with a diagnosis of stable anginashould assess thyroid and kidney function, lipid pro-file, glycemia and blood count to limit disease pro-gression (controlling risk factors) and ischemiatriggers (anemia, hyperthyroidism).6-17 These examsshould be repeated at least every year during follow-up4,17,152 (Table 4).

ECG should be repeated every year and in case ofanginal symptoms modification, onset of syncope orpre-syncope or symptoms compatible with arrhyth-mias, assumption of new drugs with possible second-ary abnormalities of electrical conduction.6 If nothingemerges from basal ECG, stress test should be per-formed to investigate potential progression of coro-nary artery disease or possible stent or graft stenosis.

During follow-up echocardiography should beconsidered only in case of clinical suspicion: onset orworsening of heart failure or valve disease, evidenceof new ischemia.17,152

Stress test are useful to demonstrate a suspectedclinical diagnosis of angina and to stratify severity.6,158

Stress ECG and echocardiography are the most usedfor their simplicity, low cost and wide-spread avail-ability, whereas stress MR and scintigraphy are not soavailable outside of academic practice settings.158

However MR is recommended in patients in whom,despite the use of echo contrast agents, transthoracicechocardiography cannot be reliable for restrictedacoustic window.6 When choosing the most appropri-ate test for a specific patient, clinician should considerpatient characteristics, potential contraindications totesting, limitations of each modality, local availabilityand local expertise.4

Angiography is useful in case of symptomatic pa-tients in optimal medical therapy to evaluate the pos-sibility of a revascularization therapy. It can beperformed in asymptomatic patients with suspectedthree vessels or left main coronary anatomy,157 be-cause medical treatment is inferior to invasive revas-cularization such as CABG in this setting. Anotherdebatable indication is represented by high-risk pa-



Table 4. Main tests in stable ischemic heart disease.

Test Utility Indication

Blood exams Control disease progression and ischemia triggers Every patient, every year

ECG Discover ischemic signs and prognosis Every patient, every year

Echocardiography Exclude other cardiopathy and evaluate ejection fraction Every patient

Stress test Diagnosis and stratification When PTP is <85% or follow-up of high risk patients

Angiography Revascularization or anatomy investigation Uncontrolled symptoms or possible complex lesions or high risk patients

ECG, electrocardiogram; PTP, termed pre-probability.

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Table 5. Stratification of risk outcome.

Non-invasive test High-risk outcome

Exercise Treadmill >2 mm of ST depression at low workload Exercise-induced ST elevation Exercise-induced ventricular tachycardia/fibrillation Failure to increase blood pressure >120 mmHg or sustained decrease >10 mmHg during exercise

Myocardial perfusion imaging Resting perfusion abnormalities >10% of the myocardium Stress-induced perfusion abnormalities >10% of the myocardium or indicating multiple coronary obstruction Severe stress-induced left ventricular dysfunction

Stress echocardiography Inducible kinetic abnormalities involving >2 coronary beds Kinetic abnormalities developing at low dose of dobutamine

Coronary computed tomographic angiography Multi-vessel or left main stenosis

Figure 2. Correct management of chest pain. ECG, electrocardiogram; EF, ejection fraction; CCTA, coronary computedtomography angiography; PTP, termed pre-probability.Non

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tients and this common practice is underinvestigation.158 LVEF, ischemic and anatomic burdenare the fundamental triad which offers prognosticstratification of patient with stable IHD4 (Table 5).

Optimal medical therapy

Lifestyle modifications and risk factors control areessential aspects to emphasize.6 Further therapy isbased on anti-anginal drugs and drugs for secondaryprevention of cardiovascular disease.43,44 The formertreatment is based on decreasing oxygen consumption:β-blockers and calcium channel blockers represent themain stems.6,157 Clinicians should choose treatment ac-cording to contraindication or patient preference. β-blockers are preferable in case myocardial infarcthistory, because these drugs demonstrated a favorableeffect on mortality.159

Long acting nitrates, ranolazine, ivabradine, nico-randil are possible second line alternative treatmentswhenever first line treatments are contraindicated orare not tolerated.6 Comorbidities, contraindications,person’s preference and drug costs are the elements to

evaluate for appropriate drug prescription. A tripleanti-anginal therapy should be considered only in pa-tients complaining persisting symptoms and present-ing non-revascularizable CHD.157

Secondary cardiovascular prevention aims to re-duce long-term risk of cardiovascular events. Statinsand low dose of aspirin should be prescribed to everypatient with stable coronary artery disease, after hav-ing considered allergies, intolerance and risk of bleed-ing.6,63-65 Aspirin reduces myocardial infarct incidencebut not fatal events. At the same time its use is associ-ated with an increased risk of bleeding.160,161 For thesereasons this treatment should be introduced after hav-ing considered bleeding risk and comorbidity. ACE-inhibitors are not routinary prescribed in patients withstable coronary artery disease67 because their advan-tages are limited to other settings such as heart failure,hypertension and myocardial infarction.

Medical treatment or invasive approach?

A clear and undebatable indication for an invasiveapproach is persisting symptoms in optimal ther-



Figure 3. Angiography indications. EF, ejection fraction; PCI, percutaneous coronary intervention; CABG, coronaryartery by-pass grafting.

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apy4,6,17,157 (Figure 3). Actually coronary artery revascu-larization with either CABG or PCI should be per-formed in symptomatic patients, uncontrolled withoptimal medical therapy or in case revascularizationcould improve survival (left main coronary artery dis-ease; three vessel disease, coronary artery disease, par-ticularly with a reduced left ventricular ejection fraction(usually <40 percent); or two vessel disease with morethan a 75 percent stenosis in the left anterior descendingartery proximal to the first major septal artery).102-108

However this last indication is based on randomized tri-als of CABG versusmedical treatment that were carriedout over 30 years ago, when statins and renin-an-giotensin system inhibitors were not available.

If revascularization is desirable, clinician shouldconsider risks and benefits of CABG and PCI, sever-ity and complexity of the person’s coronary diseaseand other relevant clinical factors and comorbidi-ties.157 A multidisciplinary team should explain var-ious options to the patient and take account of hispreference.

If the patient has anatomically less complex coro-nary disease and does not express a preference, clini-cians should take account of the evidence that PCImay be a more cost-effective procedure. For patientswith anatomically complex three-vessel disease, withor without involvement of the left main stem, and forpeople with multi-vessel disease who have diabetes orare aged >65 years, clinicians should take account ofthe potential survival advantage of CABG over PCIwhen advising patients about the appropriate revascu-larization strategy.162

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